The overall goal of the proposed research program is to bring together a group of investigators with a spectrum of talents and scientific interests into a combined effort to study in depth a number of different aspects of uremia. The studies include a continued exploration of the events leading from normal renal function to advanced renal failure. A major focus of attention will relate to the adaptations in renal function that attend the loss of functioning nephrons. These adaptations will be approached both from the point of view of the alterations in the biologic control systems which subserve the maintenance of homeostasis, and from the cost to the organism for the adaptations. One of the key elements in the study of control systems will be an extension of the ongoing search for a circulating inhibitor of sodium transport which we believe may play a role in the regulation of sodium excretion not only in uremia but in health. If it proves that the "trade-off" for adaptations is the induction of abnormalities of uremia, it should prove possible to obviate these abnormalities using techniques that are detailed in the application. Dr. Arias and his associates will study the effects of chronic renal failure on the structure and function of the hepatic endoplasmic reticulum and on the structure and function of hepatic and renal ligandin particularly as regards renal organic anion transport. In these studies, the animals and the experimental protocols used by the Nephrology group will be of major importance.